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2 general outcomes of xenobiotic metabolism

1. termination: loss of therapeutic or toxic activity
2. bioactivation: gain in therapeutic or toxic activity


sites of metabolism throughout the body

-GI tract


what does first pass metabolism refer to?

the liver is the first organ perfused by compounds absorbed in the gut (oral compounds) -> go through here before entering the circulation (affects dose needed)


definition of oral bioavailability

fraction of total dose that reaches systemic circulation


4 factors affecting bioavailability

-membrane permeability
-P-glycoprotein efflux
-pre-systemic first pass metabolism (intestinal, hepatic)


two phases of drug metabolism

I: chemical modification/biotransformation to introduce new functional group or expose group for phase II rxns

II: conjugation of polar group with drug (often kills activity)


what is the importance of drug metabolism?

frequently the most important determinant of duration and intensity of drug response
-alters pharmacological activities of drugs
-influences half-life


3 ways to terminate xenobiotic action



2 ways in which metabolism causes bioactivation

-toxification (particularly via phase I rxns)


bioinactivation vs. detoxification

terminology has more to do with intent:
-bioinactivation -> stop action of therapeutic drugs
-detoxification -> elimination of toxicity of a toxin


how does metabolism change drugs to aid in elimination?

increase polarity of the drugs:
-decrease lipid solubility
-increase water solubility



definition of prodrug

drug metabolite(s) may be more active than the parent compound, or the parent may require activation for the biological activity (bioactivation)


example of toxification

polyaromatic hydrocarbons from cigarette smoke: phase I enzymes metabolize them into planar epoxide compounds, which can intercalate into DNA (mutagenic) --> thought to be the basis of carcinogenicity of cigarette smoke


why are most adverse reactions related to drug metabolism idiosyncratic (unpredictable)?

b/c there are many poorly understood factors:
-which proteins react with reactive metabolite?
-which protein modifications lead to toxicity and how?
-many risk factors influence reactive metabolite formation and inactivation


most frequent reason that new therapeutic agents are not approved by FDA?

drug-induced hepatic damage


reactions that occur in phase I metabolism

typically oxidation
-also reduction, hydrolysis


typical enzyme of phase I reactions? what other substrates are necessary?

cytochrome P450 (CYP)
-utilizes NADPH and O2


what happens to the metabolites of phase I reactions? 2 possible outcomes

1. excreted if sufficiently polar
2. functionalized to undergo subsequent phase II rxn


what determines what the substrates will be for the CYP enzymes?

the shape of the protein determines the size/shape of entry and exit access pathways, which therefore determines which substrates will fit and which will not


in the cytochrome P450 system, what enzyme plays the electron transport role? where do the electrons come from?

P450 reductase, utilizing an electron from NADPH


what are the three most important/prevalent CYPs involved in human drug metabolism?



why is it therapeutically important that the CYPs are responsible for so much of drug metabolism?

significant chance for drug-drug interactions during multi-drug treatment --> when metabolized by the same CYP isoform, only one of the two drugs can be metabolized by the same CYP entity at the same time --> increased half-life, which may cause toxicity


describe the catalytic center of the CYPs

-contains an iron-heme cofactor
-iron coordinated to 4 N's of the heme, to 1 thiolate ligand from Cys, and to 1 water molecule (in native state)
-upon reduction, maximal light absorption "soret peak" at 450 nm


describe the reaction mechanism involving the catalytic iron-heme cofactor of the CYP catalytic site

ferric, low spin --> ferric, high spin --> ferrous --> ferric, hydroperoxide --> oxyferryl, compound I --> ferric --> repeat from start


describe 6 reactions catalyzed by CYPs

1. aromatic hydroxylation
2. N-oxidation (add =O onto amine group)
3. N-dealkylation (-CH3 -> -H on an amine)
4. O-dealkylation
5. Sulfoxidation (add =O to the S of an R-S-R')
6. Deamination (add -OH to a C that is also attached to an amine -> unstable -> rearranges into a ketone + releases amine)


what are some intrinsic factors that are important in determining which CYPs can catalyze which metabolic reactions?

-topography of protein binding site
-steric hindrance of the access to the catalytic heme group
-how the ligand binds
-ligand binding affinity
-intrinsic reactivity of chemical group that is in close proximity to the catalytic center
-accessibility of chemical group


what are three factors that determine binding strength?

-coordination strength with heme iron
-hydrophobic contacts with binding site of CYP
-specific contacts (H-bonds) with binding site residues


name two ways in which inhibitors may outcompete for binding sites on CYPs

-molecules with N as 6th iron-coordinating ligand have stronger affinity to the heme iron than molecules that coordinate with O or C atoms
-additional hydrophobic contacts stabilize the ligand-protein binding


does the substrate always have to do the inhibition? explain

no - sometimes the metabolite is the inhibitor rather than the substrate itself


does inhibition inhibit metabolism of all substrates of a specific CYP? give example

not necessarily - different binding site moieties
(inhibitor might block one substrate from binding, but not block another which accesses catalytic site from another entry point/route)

ex: cimetidine inhibits warfarin metabolism of CYP2C, but does not inhibit ibuprofen metabolism